JP 2002-513763 T (Patent Literature 1), JP 2002-154397 A (Patent Literature 2), and JP 2002-521489 T (Patent Literature 3) disclose CpG oligonucleotides and the method of manufacturing them.
JP 2010-504750 T (Patent Literature 4) discloses that oligonucleotides, which have lipophilic substituted nucleotide analogues out of CpG motif, cause production of interferon-α (IFN-α).
Non Patent Literature 1 discloses that the S-form stereoisomer of CpG oligonucleotide trimer promotes MAPK signal.
Non Patent Literature 2 discloses PF-3512676 (Sequence No. 119), all parts of the sequence are phosphorothioated and S-form stereoisomer. Natural oligonucleic acid is readily reduced in vivo. On the other hand, oligonucleic acid with P—S modifications is difficult to be reduced in vivo. In the oligonucleic acid with P—S modifications phosphoric acid ester bond of oligo nucleic acid (P—O bond) is replaced with phosphoric acid thioester bond (P—S bond).
The Non Patent Literature 3 discloses that the CpG oligonucleotide (oligonucleotide having a CpG sequence) activates Th1 immune path through the Toll-like receptor (TLR9). CpG oligonucleotides can be classified into three types: class A-C. In CpG oligonucleotides classified as class A, the 3′ and 5′-phosphate-binding site of the end of 1-4 bases are phosphorothioate linkages (PS-binding), shows a strong IFN-α production inducing ability. However, its effects on B cell proliferation are weak. On the other hand, CpG oligonucleotides are classified as class B and C, all the phosphate binding sites are of S, shows a strong B-cell proliferation effect. However, its IFN-α production inducing ability is not so strong. Natural oligonucleic acid consists of phosphodiester bonds (PO bond) is readily reduced in vivo.